Early Data Show Mutant CALR-Specific Monoclonal Antibody Well Tolerated in Myelofibrosis
Key claim: Early clinical data presented at ASH 2025 show that the mutant CALR-specific monoclonal antibody INCA033989 is well tolerated as monotherapy or in combination with ruxolitinib in myelofibrosis patients.
Abstract
Safety and efficacy data for the mutant calreticulin-specific monoclonal antibody INCA033989 as monotherapy or in combination with ruxolitinib in patients with myelofibrosis were presented at the 67th American Society of Hematology Annual Meeting and Exposition in December 2025. Unlike other MPN drivers such as JAK2 V617F, CALR mutations result in the production of a completely novel protein sequence, providing an opportunity to selectively direct immune responses against malignant cells while sparing normal hematopoiesis.
Why this matters
INCA033989 is the lead clinical asset for a genotype-specific immunologic strategy that exploits the CALR frameshift neoantigen unique to ~25–35% of PMF (and ET) patients — a mechanism orthogonal to JAK inhibition and offering selective targeting of malignant clones. Early tolerability as monotherapy and with ruxolitinib is the key gating signal for combination development on the JAKi backbone, positioning CALR-directed mAbs (INCA033989, JNJ-88549968) alongside CALR bispecifics (INCA035784) as a credible new pillar of subtype-specific MPN therapy.